Sympathetic β-adrenoceptors have been classified into β1-, β2- and β3-subtypes. The β-adrenoceptors are each distributed in specific tissues and have different functions.
β1-adrenoceptors are located predominantly on the heart, and stimulation of β1-adrenoceptors invokes increases in heart rate and potentiation of cardiac contractility. β2-adrenoceptors are found abundantly on smooth muscles of blood vessels, bronchi and the uterus, and stimulation of β2-adrenoceptors leads to vasodilation, bronchodilation and inhibition of uterine contraction. A variety of β1- and β2-adrenoceptor stimulants have been developed so far and utilized as cardiotonics, bronchodilators, prophylactic agents for threatened abortion or premature labor and the like.
It has been reported that β3-adrenoceptors are located in adipocytes, the brain, gall bladder, prostate, urinary bladder, intestinal tract and the like (see nonpatent literatures 1, 2, 3 and 4), and stimulation of β3-adrenoceptors promotes lipolysis, increased thermogenesis, hypoglycemic activities; hypolipidemic activities such as triglyceride lowering activities, hypocholesterolemic activities, HDL-cholesterol increasing activities and the like; antidepressive activities; urinary bladder relaxing activities; suppression of intestinal motility and the like (see nonpatent literatures 2, 5, 6 and 7). Accordingly, β3-adrenoceptor agonists are expected to be useful for treating or preventing obesity, diabetes mellitus, hyperlipidemia, depression, urinary dysfunctions, diseases caused by biliary tract hypermotility, or diseases caused by intestinal hypermotility.
Recent studies on β3-adrenoceptor agonists have been focused mainly on developing an anti-obesity or anti-diabetic agent. However, many of such β3-adrenoceptor agonists have been accompanied with adverse reactions such as increased heart rate, muscle tremors, hypokalemia and the like, which result from stimulation of β1- and/or β2-adrenoceptors. It has also been reported that activities of β3-adrenoceptor agonists differ markedly among species, and some compounds exhibit less potent stimulating activities on human β3-adrenoceptors than on those of a rodent such as rat β3-adrenoceptors (see nonpatent literature 8). Accordingly, it has been greatly desired to develop novel agents exhibiting potent stimulating activities on human β3-adrenoceptors with less adverse reactions caused by stimulation of β1- and β2-adrenoceptors.
Donaldson K. H. et al disclose compounds represented by the following general formula:
wherein Ra is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C1-6 alkoxy, C1-6 alkyl, nitro, cyano, hydroxymethyl, trifluoromethyl, —NRfRf and —NHSO2Rf in which Rf is hydrogen or C1-4 alkyl; Rb is hydrogen or C1-6 alkyl; Rc is cyano, tetrazol-5-yl or —CO2Rg in which Rg is hydrogen or C1-6 alkyl; Rd and Re are independently hydrogen, C1-6 alkyl, —CO2H, —CO2C1-6 alkyl, cyano, tetrazol-5-yl, halogen, trifluoromethyl or C1-6alkoxy (see patent literature 1). However, these compounds have unsatisfactory stimulating activities and selectivity on β3-adrenoceptors.Nonpatent Literature:    1. Berkowitz D E. et al, “Eur. J. Pharmacol.”, 1995, vol. 289, p. 223-228;    2. Howe R., “Drugs of the Future”, 1993, vol. 18(6), p. 529-549;    3. Ponti F D. et al, “Pharmacology”, 1995, vol. 51, p. 288-297;    4. Rodriguez M. et al, “Brain res. Mol. Brain res.” 1995, vol. 29(2), p. 369-375;    5. Simiand J. et al, “Eur. J. Pharm.”, 1992, vol. 219, p. 193-201;    6. Igawa Y. et al, “The Japanese Journal of Urology”, 1997, vol. 88(2), p. 183;    7. Igawa Y. et al, “Neurourol. Urodyn.”, 1997, vol. 16(5), p. 363-365;    8. Furutani Y., “Endocrinology & Diabetology”, 2001, vol. 12(4) p. 416-422Patent Literature:    1. International Publication No. WO99/65877 pamphlet